The wHole Story About Fenestrations in LSEC

Abstract

The porosity of liver sinusoidal endothelial cells (LSEC) ensures bidirectional passive transport of lipoproteins, drugs and solutes between the liver capillaries and the liver parenchyma. This porosity is realized via fenestrations – transcellular pores with diameters in the range of 50–300 nm – typically grouped together in sieve plates. Aging and several liver disorders severely reduce LSEC porosity, decreasing their filtration properties. Over the years, a variety of drugs, stimulants, and toxins have been investigated in the context of altered diameter or frequency of fenestrations. In fact, any change in the porosity, connected with the change in number and/or size of fenestrations is reflected in the overall liver-vascular system crosstalk. Recently, several commonly used medicines have been proposed to have a beneficial effect on LSEC re-fenestration in aging. These findings may be important for the aging populations of the world. In this review we collate the literature on medicines, recreational drugs, hormones and laboratory tools (including toxins) where the effect LSEC morphology was quantitatively analyzed. Moreover, different experimental models of liver pathology are discussed in the context of fenestrations. The second part of this review covers the cellular mechanisms of action to enable physicians and researchers to predict the effect of newly developed drugs on LSEC porosity. To achieve this, we discuss four existing hypotheses of regulation of fenestrations. Finally, we provide a summary of the cellular mechanisms which are demonstrated to tune the porosity of LSEC.

Tuning of Liver Sieve: The Interplay between Actin and Myosin Regulatory Light Chain Regulates Fenestration Size and Number in Murine Liver Sinusoidal Endothelial Cells

“…Data on isolated LSEC provide in-depth insights into the structure, dynamics, and regulation of fenestrations. During the last few decades, several crucial discoveries were made about cellular regulation of fenestrations [ 12 ]. Fenestrations were shown to be inducible structures—their number and diameter could be altered using chemical stimulation [ 13 ].…”

“…In particular, the treatment with cytochalasin B was reversible within an hour by removing the agent [ 13 ]. Many other agents were also reported to affect LSEC porosity [ 12 ]. Their effects go hand in hand with the simultaneous remodelling of the actin cytoskeleton.…”

Phenotypic Characterization of Liver Sinusoidal Endothelial Cells on the Human Liver-Chip for Potential in vitro Therapeutic Antibody Pharmacology Applications

“…SEM is the gold standard for visualizing the ultrastructure of cells and reveals that 2-20% of the LSEC surface is covered with fenestrae that are either individually scattered or arranged in a sieve-like pattern [32] with no basement membrane, and no cytoplasmic projections such as filopodia [33]. Fenestrations are characteristic transcellular pores that allow for the uptake of small molecules from the blood to the surrounding hepatocytes and vice versa [34]. However, visualizing LSEC fenestrae through SEM is historically difficult due to the loss of fenestrations within hours of isolation and culture [35].…”

“…Similar LSEC morphology was demonstrated by donor one in a liver organoid model [23] and by donor three in human coculture [25], [30] and quad-culture [24] Liver-Chips, respectively. SEM is the gold standard for visualizing the ultrastructure of cells and reveals that 2-20% of the LSEC surface is covered with fenestrae that are either individually scattered or arranged in a sieve-like pattern [32] with no basement membrane, and no cytoplasmic projections such as filopodia [33]. Fenestrations are characteristic transcellular pores that allow for the uptake of small molecules from the blood to the surrounding hepatocytes and vice versa [34].…”

Enrichment Methods for Murine Liver Non-Parenchymal Cells Differentially Affect Their Immunophenotype and Responsiveness towards Stimulation

“…LSECs form the lining of hepatic sinusoids and are characterized by numerous pore-like structures, termed fenestrae, which allow the rapid transport of, e.g., lipoproteins from hepatocytes into the sinusoidal blood stream [ 23 ]. Furthermore, LSECs release vasodilatory mediators upon shear stress, and impaired generation of these factors has been implicated in non-alcoholic fatty liver disease [ 24 ].…”